Sant Chawla MD Director Sarcoma Oncology Center Santa Monica California Financial Disclosures Advisor Research Support and Travel Grant CytRx Threshold Pharmaceuticals GlaxoSmithKline ID: 205708
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DRUG CONJUGATES BIND COVALENTLY TO ALBUMIN: A NEW APPROACH
Sant
Chawla, M.D.
Director, Sarcoma Oncology Center
Santa Monica, CaliforniaSlide2
Financial Disclosures
Advisor, Research Support, and Travel Grant
CytRx
Threshold Pharmaceuticals
GlaxoSmithKline
AmgenSlide3
The Importance of Albumin
Most abundant protein in human blood plasma
Transports hormones, fatty acids, metal ions, drugs
Buffers pH; T ½ = 20 days
Advanced cancers are nitrogen and nucleotide
“hungry“Can lead to protein catabolism ALBUMIN IS THE MAJOR SOURCE OF ESSENTIAL AMINO ACIDS FOR CANCER CELLSUtilize the Enhanced Permeability and Retention effect for macromoleculesSlide4
Enhanced Permeation and Retention effect (EPR)
Small
molecules
Y
. Matsumura, H. Maeda,
Cancer Res.
46
, 6387,
1986.
Physiological
property of solid
tumors
50 -300 nm
Healthy tissue
Blood streamSlide5
Factors Affecting the EPR Effect of Macromolecular Drugs in Solid Tumors
Active angiogenesis and high vascular density
Extensive
production of vascular mediators that facilitate extravasation, including
Bradykinin
, nitric oxide, VPF/VEGF, prostaglandins, matrix metalloproteinasesDefective vascular architecture: Lack of smooth muscle layer cells, lack of or reduced receptors for angiotensin II, large gap in endothelial cell–cell junctions, anomalous conformation (branching or stretching etc.).Impaired lymphatic clearance of macromolecules and lipids from interstitial tissue causes retentionSlide6
Tumor relevant albumin-binding proteins gp60 and SPARC
Schnitzer JE, Oh P. Antibodies to SPARC inhibit albumin binding to SPARC, gp60, and microvascular endothelium, Am J Physiol. 1992 263:1872-9
Vessel lumen
Albumin
gp60
receptor
SPARC
Endothelial cell
Tumor
interstitium
Tumor cells Slide7
Targeting Tumors Using Endogenous Albumin
Presented by:
Sant
Chawla, M.D.
Acid-sensitive linker coupled to doxorubicin
binds covalently to circulating albumin in < 5 minutes
Drug
Linker
Predetermined
Breaking point
Albumin
After infusion, linker forms covalent bond to cysteine-34 on albumin
Able to deliver several times more drug because drug is inactive until released at the tumor
Linker
can be used with many types of cancer drugs:
anthracyclines
,
taxanes
,
camptothecins
,
platinums
, etc.Slide8
Mechanism of Aldoxorubicin
Drug / linker conjugate
is infused into the patient
Tumor
cells
Albumin transports drug to the tumor and is taken up by the tumor
Linker dissolves in the acidic (low pH) environment,
releasing the drug payload
Linker
forms a covalent
bond within minutes to the
cysteine-34 of serum
albumin
1
2
3
4
Dox
Linker
Dox
Linker
Albumin
Aldoxorubicin
a
llows fo
r
3.5x
t
he standard dose of doxorubicin at
e
ach cycleSlide9
Linker-dye conjugate binds to albumin and preferentially collects in the tumor
Free dye,
no linker
Albumin bound dye
24 hour post IV infusion in SC colon tumor (LS174T) Slide10
Aldoxorubicin First-line STS Phase 2b Trial Design
Screened
N=140
2:1 Randomization N=123
Aldoxorubicin
350mg/m2(260mg/m2 dox equiv.)Every 3wk up to 6 cycles
N=83
Doxorubicin
75mg/m
2
Every 3wk up to 6
cycles
N=40
3 subjects randomized but not dosed
14 screen failures
CT Scans every 6 weeksSlide11
Patient Characteristics
Characteristics
Aldoxorubicin
Doxorubicin
N
83
40
Age, median (range)
54.0 (21-77)
54.0 (23-77)
Male / Female,
n (%)
46 /
54
45 / 55
Race, n (%)
Caucasian
74
80
Black or African American
1
2.5
Asian
19
15
Other
6
2.5
ECOG,
n (%)
0-1
96
92
2
4
8
Completed Cycles, median (range)
6 (1-6)
4 (1-6)Slide12
Disease Characteristics
Presented by:
Sant
Chawla, M.D.
Histopathology
(as determined by investigator)
Aldoxorubicin
N = 83
Doxorubicin
N = 40
Leiomyosarcoma, (%)
34
35
Liposarcoma,
(%)
16
15
Fibrosarcoma
, (%)
14
10
Synovial sarcoma,
(%)
6
10
Other
s, (%)
30
30Slide13
PFS Results
All Subjects
Intent-to-treat
P Value
Scans Read by Investigator
Aldoxorubicin
8.4 months
P=0.0004
Doxorubicin
4.7 months
Improvement over dox
3.7 mos. (79%)
Hazard ratio
0.419
(0.25-0.69)
P=0.0007
Scans Read by Central Lab
Aldoxorubicin
5.7 months
P=0.014
Doxorubicin
2.8 months
Improvement over dox
2.9 mos. (104%)
Hazard ratio
0.584
(0.37-0.93)
P=0.024Slide14
K-M Curve - Investigator Assessment
3.7 month improvement
HR: 0.419,
p=0.0007Slide15
K-M Curve – Central Lab Assessment
2.9 month improvement
HR: 0.584, p=0.024Slide16
PFS at 6 Months Results
All Subjects
Intent-to-Treat
P Value
Scans Read by Investigator
Aldoxorubicin
68.1%
P=0.002
Doxorubicin
36.6%
Improvement over dox
86.1%
Scans Read by Central Lab
Aldoxorubicin
45.7%
P=0.02
Doxorubicin
22.9%
Improvement over dox
99.6%Slide17
Overall Response Rate Results
Aldoxorubicin
Doxorubicin
Scans Read by Investigator
Complete Response
2.4%
0%
Partial Response
19.3%
5.0%
Overall Response Rate
21.7%
5.0%
Scans Read by Central Lab
Complete Response
0%
0%
Partial Response
23.8%
0%
Overall Response Rate
23.8%
0%Slide18
Waterfall Plot - Investigator
Aldoxorubicin
64.5% had tumor shrinkage
Doxorubicin
41.2% had tumor shrinkageSlide19
Waterfall Plot – Blinded Central Lab
Aldoxorubicin
60.8% had tumor shrinkage
Doxorubicin
39.4% had tumor shrinkageSlide20
Overall Survival - Preliminary
Too early to determine OS due to prolonged survival of patients in study.
As of September 15, 2014:
Higher % deaths and lower % still being followed in doxorubicin-treated subjects.
Lower % deaths and higher % still being followed in aldoxorubicin-treated subjects.
% Deaths
% Lost to F/U
% Still Followed
Aldoxorubicin
42
19
39
Doxorubicin
55
18
27Slide21
Comparison to Current STS Treatments
CytRx
Phase 2b
Investigator assessed
EORTC
Phase 3
Dox vs. dox+ ifosfamide
Aldox
Dox
Dox+ ifos
Dox
N
83
40
215
217
PFS (months)
8.4
4.7
7.4
4.6
P value
0.0004
0.003
ORR
21.7%
5.0%
26.5%
13.6%Slide22
Grade 3/4 TEAEs
Aldoxorubicin
Doxorubicin
N=83
N=40
Event
(%)
(%)
Neutropenia
40
20
Neutropenic
fever
15.7
17.5
Thrombocytopenia
6
5
Anemia
13.2
20
Nausea/vomiting
7.2
0
Mucositis
10.8
2.5
Fatigue/weakness
6.0
5.0Slide23
Cardiac Evaluation
Aldoxorubicin
Doxorubicin
% subjects with ≥15% decrease in LVEF
11%
22%
% subjects with ≥15% increase in LVEF
15%
3%
% subjects with ≤50% of expected value
0%
9.4%Slide24
ConclusionsAldoxorubicin significantly increases PFS, PFS at 6 months and ORR compared to doxorubicin therapy for first line STS.
Grade 3 or 4 neutropenia,
mucositis
and nausea/vomiting are higher in aldoxorubicin-treated patients but are not treatment limiting.
The aldoxorubicin patients received more than 5 times the cumulative amount of doxorubicin in this study than the doxorubicin patients without any evidence of clinically relevant decreased LVEF, and in more instances an increase in LVEF, either by MUGA or echocardiogram.
A phase 3 pivotal trial under a SPA is ongoing for relapsed/refractory STS.
Presented by:
Sant
Chawla, M.D.Slide25
Aldoxorubicin Clinical Development Program
Aldoxorubicin
Preclinical
Phase 1
Phase 2
Phase 3
2
nd
-line Soft Tissue Sarcoma (STS)
1
st
- Line Soft Tissue Sarcoma
Glioblastoma
Multiforme
(GBM)
Kaposi’s Sarcoma
Small Cell Lung Cancer
Pharmacokinetic Study
Combo with gemcitabine
Combo with
ifosfamide
Phase
2 on-going
Phase
2b on-going
Phase
3
on-going
Phase
1 completed
Top-line Data announced
Phase
2 on-going
Phase 2b to start 2H 2014
Ph
1b in planning
Ph
1b in planning Slide26
Phase 3 Trial Design: 2nd-line STS
Soft tissue sarcoma patients that have relapsed or are refractory to prior chemotherapy
1:1 Randomization
N=400
Aldoxorubicin
350mg/m2(260mg/m2 dox equiv.)
Every 3weeks until disease progression
N=200
Physicians Choice:
Doxorubicin
Dacarbazine
Ifosfamide
Gemcitabine+docetaxel
PazopanibN=200
CT Scans every 6 weeksSlide27
Ending RemarkAldoxorubicin has the potential to replace doxorubicin in the chemotherapy armamentarium to treat both adult and pediatric cancers.